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ID PMID Title PublicationDate abstract
25268598 The role of TNF inhibitors in psoriatic disease. 2014 Jun In contrast to many other diseases, modern psoriasis therapy has a fairly brief history. Until about 15 years ago, clinicians and their patients had few options, with limited ability to rein in the disease process.The success of antifolate methotrexate in the treatment of rheumatoid arthritis (RA) led to clinical evaluation and adoption of the agent, a principal form of treatment for psoriasis, which, like RA, has its origin based in inflammation. The introduction of tumor necrosis factor-α inhibitors marked the beginning of the biologic era of psoriasis therapy. Also borrowed from the field of rheumatology, biologic therapy has evolved from improved understanding of the molecular basis of the disease process. An increased recognition of comorbid conditions that often accompany psoriasis, particularly psoriatic arthritis, can complicate clinical management. Dermatologists and other clinicians who treat psoriasis continue to benefit from insights gained in the field of rheumatology.
25125973 Subcutaneously administered methotrexate for rheumatoid arthritis, by prefilled syringes v 2014 PURPOSE: This multicenter, randomized, crossover study compared preference, ease of use, acceptability, satisfaction, and safety of repeated subcutaneous (SC) self-administrations with prefilled pens and prefilled syringes delivering methotrexate (MTX), in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: The study (ClinicalTrials.gov number NCT01793259) enrolled 120 patients requiring initiation or intensification of MTX therapy for RA. Patients were randomized to receive the test drug, a prefilled pen (Metex(®) PEN/Metoject(®) PEN), or the reference drug, a prefilled syringe (Metex(®)/Metoject(®)), at doses of 15, 17.5, or 20 mg MTX SC once a week for 3 weeks. This was followed by receipt of the reference drug (prefilled syringe) or the test drug (prefilled pen) in a crossover design, with each patient serving as his/her own control. Questionnaires regarding patient preference, the Self-Injection Assessment Questionnaire (SIAQ), and diaries regarding local tolerability were used to document outcomes. RESULTS: Overall patient preference for the MTX prefilled pen was 75% (P<0.0001). In a six-item questionnaire, 73% to 76% of the patients preferred the prefilled pen in relation to use, acceptability, and satisfaction, and 67% of the patients confirmed that it did not take much effort to overcome SC self-injection with the pen. The SIAQ showed no clinical differences, in any domain scores, between both devices. Overall patient attitude towards self-injection at baseline was positive, as was patient experience with both devices during the study. As well, 92% of physicians and study nurses indicated that they would recommend the MTX prefilled pen to patients for future MTX treatment. The formulations were generally well tolerated. CONCLUSION: SC self-injection of MTX with a prefilled pen was generally preferred, by patients with RA, over a prefilled syringe with regard to use, acceptability, and satisfaction. This is supported by the strong appreciation of their attending study nurses and physicians, for its convenience.
23959753 IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid ar 2013 Aug 19 OBJECTIVES: To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab. DESIGN: Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response. RESULTS: Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response. CONCLUSIONS: Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.
23815937 [Therapeutic effect of human bone marrow mesenchymal stem cell lysates on rat arthritis in 2013 Jun Our previous work has shown that mesenchymal stem cells (MSC) have little therapeutic effect on rat arthritis induced by collagen. This study was aimed to further investigate whether the MSC lysates exhibit beneficial effects on rheumatoid arthritis. Aliquots of cell lysates from 1×10(7) human bone marrow MSC were intraperitoneally injected into collagen-induced arthritis (CIA) Wistar rats weekly for 4 consecutive weeks. Methotrexate at a dose of 1 mg/kg or normal saline was served as positive and negative controls respectively. On week 4 the symptom scores were recorded and the hind joints of the rats were pathologically examined and X-ray examination was performed. The results showed that on week 4, the symptom scores of the rats that received MSC lysates (6.87 ± 0.83) and MTX (6.44 ± 1.13) were significantly lower than that of control rats (7.33 ± 0.77, P < 0.01). Meanwhile, pathological examination on the involved ankle showed that the synovitis and arthritis scores of MSC lysates and control groups were 2.28 ± 0.48 and 2.28 ± 0.55 respectively, significantly higher than that of MTX treatment rats (0.71 ± 0.48, P < 0.05). However, X-ray examination on the ankle joints showed that the injury score of control rats was 4 ± 0.57, greatly higher than those from MSC lysates (2.71 ± 0.75) and MTX treatment groups (2.57 ± 0.78, P < 0.05 for both groups). It is concluded that MSC lysate infusion has beneficial effects on CIA rat, but the effectiveness seems inferior to MTX.
24909567 Distinct effects of methotrexate and etanercept on the B cell compartment in patients with 2014 Sep OBJECTIVE: B cells have been shown to play an important role in the pathogenesis of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). Current treatments include the disease-modifying antirheumatic drugs methotrexate (MTX) and tumor necrosis factor α inhibition with etanercept. This study was undertaken to determine how these drugs influence the B cell compartment in patients with JIA. METHODS: B cell subpopulations and follicular helper T (Tfh) cells in the peripheral blood of JIA patients were investigated by multicolor flow cytometry. Serum immunoglobulin and BAFF levels were determined by enzyme-linked immunosorbent assay. RESULTS: There was a significant decrease in transitional B cells and significantly lower serum immunoglobulin levels in patients receiving MTX than in untreated patients and those receiving etanercept. In contrast, etanercept treatment had no effect on most of the B cell subpopulations, but resulted in significantly lower BAFF levels and increased numbers of Tfh cells. Thus, our findings indicate an unexpected and previously unknown direct effect of low-dose MTX on B cells, whereas etanercept had a more indirect influence. CONCLUSION: Our results contribute to a better understanding of the potency of MTX in autoantibody-mediated autoimmune disease and present a possible mechanism of prevention of the development of drug-induced antibodies to biologic agents. The finding that MTX and etanercept affect the B cell compartment differently supports the notion that combination therapy with etanercept and MTX is more effective than monotherapy.
24278124 Targeting TNF-α and NF-κB activation by bee venom: role in suppressing adjuvant induced 2013 Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. CONCLUSION: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB.
23565631 Effects of biologic agents and other disease-modifying antirheumatic drugs on cardiovascul 2014 BACKGROUND: Whether systemic treatments for psoriasis or psoriatic arthritis affect cardiovascular comorbidities is a clinically significant question. OBJECTIVE: To examine the effects of biologic agents and other Disease-Modifying Antirheumatic Drugs (DMARDs) used to treat psoriasis and psoriatic arthritis on cardiovascular risk factors and adverse cardiovascular outcomes. METHODS: MEDLINE (1980-October 2012), Web of Science, the EULAR abstract database, and the AAD annual meeting abstract archive were searched for studies evaluating biologic and other DMARD therapy for psoriasis and psoriatic arthritis that reported cardiovascular events as primary outcomes. RESULTS: From 20 studies that met the search criteria for the review, 81,469 patients with psoriasis and/or psoriatic arthritis were included in the data synthesis of the current literature. While the data on the cardioprotective effect of methotrexate exist in patients with rheumatoid arthritis, its effect on the psoriasis and psoriatic arthritis populations with regards to cardiovascular outcomes are inconclusive at this time. The association of hypertension with long-term cyclosporine use prompts discontinuation of cyclosporine in selected patients. The use of TNF inhibitors may be associated with reduced risk of adverse cardiovascular events in preliminary epidemiologic studies; however, large randomized controlled trials and epidemiologic studies with well-characterized populations will be necessary to elucidate their exact effects. The short-term data regarding the safety of IL-12/23 inhibitors showed that, to date, there are no increased cardiovascular events compared to the general population. CONCLUSIONS: To date, epidemiologic data is insufficient to reach definitive conclusions with regards to the effects of biologics and other DMARDs on cardiovascular outcomes in psoriasis and psoriatic arthritis patients. Adequately powered, long-term, controlled studies are necessary to determine the cardioprotective effects of TNF inhibitors observed in preliminary studies on psoriasis and psoriatic arthritis populations.
25398063 Myocarditis in adult-onset still disease. 2014 Oct This study highlights the clinical features, treatments, and outcomes of the rare myocarditis in adult-onset Still disease (AOSD). Among a case series of 57 patients fulfilling either Yamaguchi or Fautrel AOSD criteria and seen between 1998 and 2010, we identified 4 cases of myocarditis. From a comprehensive literature review, we collected 20 additional cases of myocarditis-complicated AOSD. The characteristics of patients with myocarditis were compared with those of AOSD patients without myocarditis.In these 24 myocarditis-complicated AOSD cases, myocarditis occurred early and was present at AOSD onset in 54% of the cases. Myocarditis was often symptomatic (96% of patients) with nonspecific electrocardiographic abnormalities (79% of patients) and a left ventricle ejection fraction ≤50% (67% of patients). Cardiac magnetic resonance imaging and endomyocardial biopsies showed features consistent with myocarditis in 4 patients and a mononuclear interstitial inflammatory infiltrate in 4 others. Steroids alone were effective in 50% of patients with myocarditis. Intravenous immunoglobulins, methotrexate, and tumor necrosis factor-α-blockers were also prescribed and often found effective. Only 1 patient died from cardiogenic shock. Patients with myocarditis-complicated AOSD were younger and more frequently male than patients with AOSD alone. Pericarditis was more frequent in the myocarditis group; white blood cell count, polymorphonuclear cell count, and serum ferritin levels were also higher.Myocarditis is a potentially life-threatening complication of AOSD but responds positively to steroids and other immunomodulatory drugs. Its prognosis remains good (only 1 death occurred), but the condition requires close monitoring of heart function.
23124729 Leflunomide addition in patients with articular manifestations of psoriatic arthritis resi 2013 Nov In contrast to rheumatoid arthritis, in psoriatic arthritis (PsA), the efficacy of disease-modifying antirheumatic drugs (DMARDs) combination has not been documented. We conducted a retrospective study to evaluate the effectiveness of leflunomide (LEF) addition in 11 PsA patients with articular manifestations that failed to respond to methotrexate (MTX) monotherapy [disease activity score in 28 joints (DAS28) > 3.2)]. Eight of them, all with moderate disease activity (DAS28 < 5.1) at baseline, tolerated the combination. A statistically significant improvement of the mean DAS28, based on erythrocyte sedimentation rate (ESR), and its variables, and C-reactive protein (CRP) at 12-16 weeks after LEF addition was observed. Mean change of DAS28 in patients with polyarticular disease did not differ compared with those with oligoarticular. Based on the European League Against Rheumatism (EULAR) response criteria, none of our patients achieved a good response, seven had a moderate response, and one was a non-responder. The two patients with the lower DAS28 at baseline attained low disease activity (LDA, DAS28 ≤ 3.2), while none reached remission (DAS28 ≤ 2.6). Achievement of clinical remission or at least LDA has been recently proposed as the goal of treatment in PsA. Our results imply that LEF addition may serve as an alternative therapeutic modality for patients with moderately active PsA and, as lower as possible, residual disease activity after the initial therapy with MTX alone.
24892681 Life-threatening pneumonitis complicating low-dose methotrexate treatment for juvenile idi 2014 Jun Methotrexate, a drug commonly used to treat juvenile idiopathic arthritis (JIA), has been reported to cause interstitial pneumonitis as a rare complication in adults with rheumatoid arthritis. Only 1 suspicious case of methotrexate pneumonitis in a child with JIA has been reported in 1998, though with no histopathologic proof. Given its rarity and nonspecific presenting symptoms, diagnosis may be challenging, and a life-threatening illness can occur without a high index of suspicion, as illustrated by this report of a 13-year-old girl with JIA who developed fever, nonproductive cough, and dyspnea as presenting features of interstitial pneumonitis after 1 year of methotrexate therapy. Chest high-resolution computed tomography revealed patchy ground-glass opacities and interlobular septal thickening without pleural effusion. Lung biopsy showed interstitial pneumonitis with diffuse alveolar damage. The symptoms and radiographs improved dramatically after withdrawal of methotrexate and administration of corticosteroids. A restrictive ventilatory defect with decreased diffusion capacity on pulmonary function testing persisted until 20 months after methotrexate withdrawal. There is no single pathognomic feature for methotrexate pneumonitis; rather, diagnosis relies on a constellation of clinical, radiologic, and pathologic findings. This report highlights the necessity for pediatricians to be continuously vigilant for interstitial pneumonitis in children receiving methotrexate who develop new unexplained pulmonary symptoms.
24088343 Pulmonary hypertension secondary to hyperviscosity in a patient with rheumatoid arthritis 2013 Oct 2 INTRODUCTION: Acquired von Willebrand disease is initiated by autoantibodies and hyperviscosity syndrome caused by a massive polyclonal hypergammaglobulinemia. Acquired von Willebrand disease associated with autoimmune disease in addition to pulmonary hypertension during emergency room presentation is a rare condition. To the best of our knowledge, this is the second case reported in the literature treated with success; the first one was reported in 1987. CASE PRESENTATION: A 28-year-old mestizo man with a 3-year history of inflammatory arthritis was admitted to our hospital. An overlap of rheumatoid arthritis with systemic lupus erythematosus was suspected; therefore methotrexate was initiated, and later changed to leflunomide because of liver toxicity. Prothrombin time, international normalized ratio and activated partial thromboplastin times were normal (11/10.4 seconds; 1.2; 31.1/26.9 seconds, respectively), von Willebrand factor activity was observed with low ristocetin cofactor at 33.6UI/dL, high von Willebrand factor antigen >200UI/dL, and a low von Willebrand factor: ristocetin cofactor to von Willebrand factor antigen ratio. He was admitted to the emergency room with a 24-hour evolution of progressive dyspnea, cough, thoracic pain, and palpitations, 104 beats/min, 60/40 mmHg, temperature of 38°C, pulse oximetric saturation 88% and 30 breaths/minute. Cold, pale and mottled skin was also observed. He was then transferred to the intensive care unit. The placement of a pulmonary artery catheter was made. The initial patterns showed a precapillary pulmonary hypertension; acute pulmonary embolism was the first choice for diagnosis. Pulmonary angiography was conducted, and when no clot was discovered, pulmonary artery hypertension associated with connective tissue disease was considered. Serum protein electrophoresis confirmed the presence of a massive polyclonal hypergammaglobulinemia, and no paraproteinemia or monoclonal cell population was found from the electrophoretic pattern of the patient's plasma. Hypergammaglobulinemia was the cause of hyperviscosity syndrome associated with autoantibodies. Three sessions of plasma exchange therapy were made, and clinical improvement was observed. He was then discharged from the intensive care unit and hospital, respectively. He is now attended by an external consult and has no respiratory symptomatology. CONCLUSIONS: Hyperviscosity syndrome with pulmonary arterial hypertension presentation in a patient with acquired von Willebrand disease in an autoimmune context is a rare condition that can be treated successfully with plasmapheresis and critical care support.
24348567 Rheumatoid factor positivity is associated with increased joint destruction and upregulati 2013 We evaluated changes in gene expression of mTOR, p21, caspase-3, ULK1, TNF α , matrix metalloproteinase (MMP)-9, and cathepsin K in the whole blood of rheumatoid arthritic (RA) patients treated with methotrexate (MTX) in relation to their rheumatoid factor status, clinical, immunological, and radiological parameters, and therapeutic response after a 24-month follow-up. The study group consisted of 35 control subjects and 33 RA patients without previous history of MTX treatment. Gene expression was measured using real-time RT-PCR. Decreased disease activity in patients at the end of the study was associated with significant downregulation of TNF α expression. Downregulation of mTOR was observed in seronegative patients, while no significant changes in the expression of p21, ULK1, or caspase-3 were noted in any RA patients at the end of the study. The increase in erosion numbers observed in the seropositive patients at the end of the follow-up was accompanied by upregulation of MMP-9 and cathepsin K, while seronegative patients demonstrated an absence of significant changes in MMP-9 and cathepsin K expression and no increase in the erosion score. Our results suggest that increased expression of MMP-9 and cathepsin K genes in the peripheral blood might indicate higher bone tissue destruction activity in RA patients treated with methotrexate. The clinical study registration number is 0120.0810610.
24038004 Acute exacerbation in rheumatoid arthritis-associated interstitial lung disease: a retrosp 2013 Sep 13 OBJECTIVES: To investigate the risk factors and prognosis associated with acute exacerbation (AE) in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). DESIGN: A retrospective case-control study. SETTING: A single academic hospital. PARTICIPANTS: 51 consecutive patients diagnosed with RA-ILD between 1995 and 2012. All patients fulfilled the diagnostic criteria of the American College of Rheumatology for RA. ILD was diagnosed on the basis of clinical presentation, pulmonary function tests, high-resolution CT (HRCT) findings and lung biopsy findings. MAIN OUTCOME MEASURES: Overall survival and cumulative AE incidence were analysed using Kaplan-Meier method. Cox hazards analysis was used to determine significant variables associated with AE occurrence and survival status. RESULTS: A total of 11 patients (22%) developed AE, with an overall 1-year incidence of 2.8%. Univariate analysis revealed that older age at ILD diagnosis (HR 1.11; 95% CI 1.02 to 1.21; p=0.01), usual interstitial pneumonia (UIP) pattern on HRCT (HR 1.95; 95% CI 1.07 to 3.63; p=0.03) and methotrexate usage (HR 3.04; 95% CI 1.62 to 6.02; p=0.001) were associated with AE. Of 11 patients who developed AE during observation period, 7 (64%) died of initial AE. In survival, AE was a prognostic factor for poor outcome (HR 2.47; 95% CI 1.39 to 4.56; p=0.003). CONCLUSIONS: In patients with RA-ILD, older age at ILD diagnosis, UIP pattern on HRCT and methotrexate usage are associated with the development of AE. Furthermore, AE has a serious impact on their survival.
23651163 Methotrexate: should we start using it in clinical practice? 2013 Nov Therapeutic approaches in inflammatory bowel disease have changed significantly in the past decade. Early aggressive immunosuppression has become the mainstay of therapy for patients at risk for complicated disease. Azathioprine is the most widely used immunosuppressant; however, a subgroup of patients is intolerant or refractory. Since the late 1990s, methotrexate (MTX) has become more widely used as an immunomodulator in patients with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. Yet according to recent clinical data, methotrexate remained the second most commonly used immunosuppressive in inflammatory bowel diseases. Two landmark trials and subsequent studies provided evidence for the use of methotrexate in Crohn's disease, both for induction and maintenance of remission. The evidence is less solid in ulcerative colitis, for which results of further randomized controlled trials are pending (e.g. Meteor, Merit). A potential new indication of MTX could be combination therapy with biologicals. While this is state of the art therapy in rheumatoid arthritis, data in inflammatory bowel diseases are less clear. Some studies suggest that combination with immunosuppressants could prevent the development of anti-drug antibodies, while others suggested anti- TNF induced autoimmune disorders as a potential indication. In contrast, improved efficacy was not reported by one study (COMMIT). Limitations include frequent side effects, route of administration, pregnancy and concerns about long-term safety. This review summarizes current knowledge on the efficacy and side effects of methotrexate, and tries to reevaluate the drug in the current IBD armamentarium.
23562815 A retrospective cohort study: 10-year trend of disease-modifying antirheumatic drugs and b 2013 OBJECTIVES: To evaluate the trends in patterns of disease-modifying antirheumatic drugs (DMARDs) and biological agents use from 1999 to 2009 and to identify patient characteristics associated with different patterns of their use in a national sample of Veterans with rheumatoid arthritis (RA). DESIGN: A retrospective cohort study. SETTINGS: Administrative databases of the USA Department of Veterans Affairs. PARTICIPANTS: An incident cohort of 13 254 patients with newly diagnosed RA was identified. PRIMARY OUTCOME MEASURES: Trends and choice of DMARDs and biological agents' usage, and time intervals between RA diagnosis and treatment RESULTS: Methotrexate use as first-line agent increased from 39.9% to 57.2% over the study period (p<0.001). Although biological dispensations increased over other DMARDs and biological agents, from 3.4% to 25% from 1999 to 2009, the percentage of RA patients diagnosed between 1999 and 2007 who had biologics dispensations remained steady at 23.3-26.7%. Compared with Caucasian, African Americans were less likely to receive biologics (HR 0.71, 95% CI 0.63 to 0.81). Patients aged 75 and older were less likely to receive biologics than those younger than 45 (HR 0.29, 95% CI 0.23 to 0.36). The time interval between RA diagnosis and treatment with DMARDs and biological agents decreased significantly over time (median: 51 days in 1999-2001 to 28 days in 2006-2007). CONCLUSIONS: Methotrexate use increased as it became the preferred first-line agent, while other traditional agents declined. Dispensation of biologics increased significantly, but the proportion of RA patients eventually given biologics stabilised below 30%. A significant shorter time between RA diagnosis and DMARD or biological agent initiation in recent years suggests improvements in quality of care. There were disproportionately lower use of biologics in certain age and ethnic groups, and further studies will be needed to elucidate these observations.
23439784 Intra-articular methotrexate associated to lipid nanoemulsions: anti-inflammatory effect u 2013 OBJECTIVE: Commercial methotrexate formulations (MTX) have poor anti-inflammatory action for intra-articular treatment of rheumatoid arthritis. Our aim was to investigate whether an association between methotrexate and lipidic nanoemulsions (LDE) could improve MTX intra-articular action. METHODS: For its association to LDE, MTX was previously esterified with dodecyl bromide. LDE-MTX was prepared by high pressure homogenization. Antigen-induced arthritis (AIA) was achieved in rabbits sensitized with methylated bovine serum albumin, and the rabbits were subsequently intra-articularly injected with the antigen. Twenty-four hours after AIA induction, groups of four to nine rabbits were intra-articularly injected with increasing doses (0.0625-0.5 μmol/kg) of LDE-MTX, and were compared to treatment with 0.5 μmol/kg commercial MTX, LDE alone, and saline (controls). Synovial fluid was collected 48 hours after AIA induction for analysis of protein leakage and cell content. Synovial membranes were collected for histopathology. Uptake of LDE labeled with (3)H-cholesteryl ether by the synovial tissue was also determined. RESULTS: Uptake of radioactive LDE by arthritic joints was 2.5-fold greater than by normal joints. Treatment with intra-articular LDE-MTX elicited a clear dose response pattern by reducing the synovial leukocyte infiltrate (P = 0.004) and protein leakage (P = 0.032) when compared with arthritic non-treated joints. In contrast, the intra-articular injection of commercial MTX and LDE did not reduce leukocyte infiltrate or protein leakage. Toxicity to treatment was not observed in any of the animals. CONCLUSION: The association between LDE and MTX presented a marked anti-inflammatory effect that was absent after intra-articular commercial MTX treatment. Therefore, the new formulation is a candidate for future clinical studies.
23117086 Evaluation of the effect of losartan and methotrexate combined therapy in adjuvant-induced 2013 Jan 5 There is increasing body of evidence documenting the involvement of angiotensin II in inflammatory diseases. Moreover the up-regulation of angiotensin II AT(1) receptors in the synovium of rheumatoid arthritis patients has been previously described. This study aimed at investigating the anti-inflammatory effect of losartan, the selective angiotensin II AT(1) receptor blocker, and comparing the efficacy of methotrexate alone and in combination with losartan in adjuvant arthritis in rats. Twelve days post adjuvant injection, Sprague-Dawley rats were treated with methotrexate (1mg/kg/week), losartan (20mg/kg/day) and their combination for 15 days. Severity of arthritis was assessed by hind paw swelling, arthrogram scores. Serum was analyzed for measurement of albumin, C-reactive protein (CRP), nitrite/nitrate concentrations, interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), aspartate transaminase (AST) and alanine transaminase (ALT). Histopathological examination was done for hind paws and livers. Methotrexate and losartan monotherapies significantly reduced all parameters of inflammation and arthritis with better results in the methotrexate group except for the transaminases where losartan caused more significant reduction in their serum levels. The combined therapy showed better results than methotrexate and losartan alone. Hind paws showed better improvement of inflammatory cell infiltration and bone resorption in the combined therapy group. Disturbances in liver architecture and fibrosis caused by adjuvant arthritis were reverted to normal status in the combined therapy group in contrast to losartan and methotrexate monotherapies. In conclusion, methotrexate and losartan combined therapy provided more effective anti-inflammatory and hepatoprotective effects than either drug alone.
24782185 Ankylosing spondylitis, psoriatic arthritis, and risk of malignant lymphoma: a cohort stud 2014 May OBJECTIVE: Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relation to therapies, including tumor necrosis factor inhibitor (TNFi), for which lymphoma risks are a concern. METHODS: Through the Swedish National Patient Register we assembled nationwide prevalence cohorts of patients with AS (n = 8,707) and patients with PsA (n = 19,283) for whom data were obtained between 2001 and 2010. Each cohort member was matched to 5 population comparator subjects. Linkage with the nationwide Cancer Register identified all lymphomas recorded from 2001 to 2010. Through the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]), we identified patients exposed to TNFi in the AS cohort (n = 1,908) and the PsA cohort (n = 2,605) before lymphoma diagnosis. Hazard ratios (HRs) for lymphoma were estimated by Cox regression. Crude incidences of lymphoma in TNFi-exposed and TNFi-naive patients were compared. RESULTS: For AS patients, the HR of having lymphoma versus the general population was 0.9 (95% confidence interval [95% CI] 0.5-1.6) (14 lymphomas). For PsA patients, the corresponding HR was 1.2 (95% CI 0.9-1.7) (45 lymphomas). For PsA patients treated with methotrexate and/or sulfasalazine, the HR of having lymphoma was 1.7 (95% CI 1.0-3.1). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and PsA patients, although the numbers of lymphomas were small. CONCLUSION: In contrast to rheumatoid arthritis, the average risks of lymphoma in AS or PsA are not elevated, although increased risks in a subset of PsA patients cannot be excluded. Our findings indicate that TNFi does not affect the risk of lymphoma in AS or in PsA.
24356481 Effect of golimumab on carotid atherosclerotic disease measures and cardiovascular events 2014 Jan OBJECTIVE: The objective of this study was to assess the effect of golimumab on carotid ultrasound measures and cardiovascular serious adverse events (SAEs) in patients with inflammatory arthritides. METHODS: An exploratory carotid artery ultrasound substudy was performed in the GO-BEFORE study of methotrexate (MTX)-naive rheumatoid arthritis patients, with ultrasounds performed at weeks 0, 24, and 52 to measure common carotid artery intima-media thickness, distensibility coefficient, interadventitial diameter, and plaque count. Cardiovascular SAEs reported over 2 years of follow-up were assessed in 5 golimumab phase 3 clinical trials of patients with rheumatoid arthritis (GO-BEFORE, GO-FORWARD, and GO-AFTER), psoriatic arthritis (GO-REVEAL), and ankylosing spondylitis (GO-RAISE). In GO-BEFORE and GO-FORWARD, patients received placebo + MTX, golimumab 50 mg + MTX, or golimumab 100 mg +/- MTX at baseline and every 4 weeks; in the other 3 trials, patients received placebo or golimumab 50 or 100 mg. RESULTS: The carotid ultrasound substudy showed inconsistent changes in common carotid artery intima-media thickness in the golimumab + MTX groups over time, and there was large variability in the measurements. Increases in interadventitial diameter were observed in the golimumab 100 mg + placebo group, but not in the golimumab + MTX groups. There were no significant differences in the distensibility coefficient and plaque count between the golimumab and placebo groups. Very few patients overall experienced a cardiovascular SAE, and the incidence of cardiovascular SAEs was not statistically different between the golimumab and placebo groups. CONCLUSIONS: The results of the carotid ultrasound substudy were inconclusive, and no increase or decrease in cardiovascular SAEs was observed following 2 years of treatment with golimumab with or without MTX.
23963988 [Orthopedic rheumatology]. 2013 Aug Rheumatic diseases with their progressive inflammatory systematic nature are important diseases any clinical practising orthopaedic doctor is frequently confronted with. In case of mono- or polyarticular joint swelling, stiffness or inflammatory arthralgia, rheumatoid arthritis has to be deliberated particularly in differential diagnostic considerations. When diagnosed early, a joint treatment by an internal specialist as well as the initiation of a basic medicamentous therapy are highly recommended. Therefore, corticosteroids and disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate can be used, in case of failure a treatment with biologicals should follow. The operative therapy depends on the stadium of joint destruction. In early stadiums (LDE 0-3) and in case of therapy resistant inflammation a synovectomy should be performed as a preventive intervention. Given an already advanced destruction, alloarthroplasty or arthrodesis are indicated as reconstructive procedures.